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1.
ACS Omega ; 7(12): 10012-10021, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35382341

RESUMO

We focus on the concentration dependency of fibril-forming peptides, which have the potential of aggregation by themselves. In this study, we performed replica-exchange molecular dynamics simulations of Lys-Phe-Phe-Glu (KFFE) fragments, which are known to form fibrils in experiments under different concentration environments. The analysis by static structure factors suggested that the density fluctuation of the KFFE fragments becomes large as the concentration increases. It was also found that the number of ß-structures and oligomers also increases under a high concentration environment. Hence, a high concentration environment of fibril-forming peptides is likely to cause protein aggregation.

2.
J Comput Chem ; 41(1): 56-68, 2020 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-31621932

RESUMO

We propose a free energy calculation method for receptor-ligand binding, which have multiple binding poses that avoids exhaustive enumeration of the poses. For systems with multiple binding poses, the standard procedure is to enumerate orientations of the binding poses, restrain the ligand to each orientation, and then, calculate the binding free energies for each binding pose. In this study, we modify a part of the thermodynamic cycle in order to sample a broader conformational space of the ligand in the binding site. This modification leads to more accurate free energy calculation without performing separate free energy simulations for each binding pose. We applied our modification to simple model host-guest systems as a test, which have only two binding poses, by using a single decoupling method (SDM) in implicit solvent. The results showed that the binding free energies obtained from our method without knowing the two binding poses were in good agreement with the benchmark results obtained by explicit enumeration of the binding poses. Our method is applicable to other alchemical binding free energy calculation methods such as the double decoupling method (DDM) in explicit solvent. We performed a calculation for a protein-ligand system with explicit solvent using our modified thermodynamic path. The results of the free energy simulation along our modified path were in good agreement with the results of conventional DDM, which requires a separate binding free energy calculation for each of the binding poses of the example of phenol binding to T4 lysozyme in explicit solvent. © 2019 Wiley Periodicals, Inc.


Assuntos
Simulação de Dinâmica Molecular , Muramidase/química , Fenóis/química , Termodinâmica , Sítios de Ligação , Ligantes , Muramidase/metabolismo
3.
Biophys J ; 116(5): 781-790, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30771855

RESUMO

A peptide ß2-m21-31, which is a fragment from residue 21 to residue 31 of ß2-microgloblin, is experimentally known to self-assemble and form amyloid fibrils. In order to understand the mechanism of amyloid fibril formations, we applied the replica-exchange molecular dynamics method to the system consisting of three fragments of ß2-m21-31. From the analyses on the temperature dependence, we found that there is a clear phase transition temperature in which the peptides aggregate with each other. Moreover, we found by the free energy analyses that there are two major stable states: One of them is like amyloid fibrils and the other is amorphous aggregates.


Assuntos
Simulação de Dinâmica Molecular , Multimerização Proteica , Microglobulina beta-2/química , Estrutura Quaternária de Proteína , Termodinâmica
4.
Sci Rep ; 9(1): 767, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683882

RESUMO

In the context of drug design, C-H···O hydrogen bonds have received little attention so far, mostly because they are considered weak relative to other noncovalent interactions such as O-H···O hydrogen bonds, π/π interactions, and van der Waals interactions. Herein, we demonstrate the significance of hydrogen bonds between C-H groups adjacent to an ammonium cation and an oxygen atom (N+-C-H···O hydrogen bonds) in protein-ligand complexes. Quantum chemical calculations revealed details on the strength and geometrical requirements of these N+-C-H···O hydrogen bonds, and a subsequent survey of the Protein Data Bank (PDB) based on these criteria suggested that numerous protein-ligand complexes contain such N+-C-H···O hydrogen bonds. An ensuing experimental investigation into the G9a-like protein (GLP)-inhibitor complex demonstrated that N+-C-H···O hydrogen bonds affect the activity of the inhibitors against the target enzyme. These results should provide the basis for the use of N+-C-H···O hydrogen bonds in drug discovery.


Assuntos
Histona-Lisina N-Metiltransferase/química , Bases de Dados de Proteínas , Ligação de Hidrogênio , Ligantes , Teoria Quântica
5.
J Comput Chem ; 40(2): 475-481, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30414195

RESUMO

We propose a molecular simulation method using genetic algorithm (GA) for biomolecular systems to obtain ensemble averages efficiently. In this method, we incorporate the genetic crossover, which is one of the operations of GA, to any simulation method such as conventional molecular dynamics (MD), Monte Carlo, and other simulation methods. The genetic crossover proposes candidate conformations by exchanging parts of conformations of a target molecule between a pair of conformations during the simulation. If the candidate conformations are accepted, the simulation resumes from the accepted ones. While conventional simulations are based on local update of conformations, the genetic crossover introduces global update of conformations. As an example of the present approach, we incorporated genetic crossover to MD simulations. We tested the validity of the method by calculating ensemble averages and the sampling efficiency by using two kinds of peptides, ALA3 and (AAQAA)3 . The results show that for ALA3 system, the distribution probabilities of backbone dihedral angles are in good agreement with those of the conventional MD and replica-exchange MD simulations. In the case of (AAQAA)3 system, our method showed lower structural correlation of α-helix structures than the other two methods and more flexibility in the backbone ψ angles than the conventional MD simulation. These results suggest that our method gives more efficient conformational sampling than conventional simulation methods based on local update of conformations. © 2018 Wiley Periodicals, Inc.


Assuntos
Algoritmos , Simulação de Dinâmica Molecular , Peptídeos/química , Conformação Proteica
6.
J Chem Phys ; 148(12): 125102, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29604890

RESUMO

We performed protein-ligand docking simulations with a ligand T247, which has been reported as a selective inhibitor of a histone deacetylase HDAC3, by the replica-exchange umbrella sampling method in order to estimate the free energy profiles along ligand docking pathways of HDAC3-T247 and HDAC2-T247 systems. The simulation results showed that the docked state of the HDAC3-T247 system is more stable than that of the HDAC2-T247 system although the amino-acid sequences and structures of HDAC3 and HDAC2 are very similar. By comparing structures obtained from the simulations of both systems, we found the difference between structures of hydrophobic residues at the entrance of the catalytic site. Moreover, we performed conventional molecular dynamics simulations of HDAC3 and HDAC2 systems without T247, and the results also showed the same difference of the hydrophobic structures. Therefore, we consider that this hydrophobic structure contributes to the stabilization of the docked state of the HDAC3-T247 system. Furthermore, we show that Tyr209, which is one of the hydrophobic residues in HDAC2, plays a key role in the instability from the simulation results of a mutated-HDAC2 system.

7.
J Cell Biol ; 217(3): 959-974, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29279306

RESUMO

The endoplasmic reticulum (ER)-mitochondrial encounter structure (ERMES) physically links the membranes of the ER and mitochondria in yeast. Although the ER and mitochondria cooperate to synthesize glycerophospholipids, whether ERMES directly facilitates the lipid exchange between the two organelles remains controversial. Here, we compared the x-ray structures of an ERMES subunit Mdm12 from Kluyveromyces lactis with that of Mdm12 from Saccharomyces cerevisiae and found that both Mdm12 proteins possess a hydrophobic pocket for phospholipid binding. However in vitro lipid transfer assays showed that Mdm12 alone or an Mmm1 (another ERMES subunit) fusion protein exhibited only a weak lipid transfer activity between liposomes. In contrast, Mdm12 in a complex with Mmm1 mediated efficient lipid transfer between liposomes. Mutations in Mmm1 or Mdm12 impaired the lipid transfer activities of the Mdm12-Mmm1 complex and furthermore caused defective phosphatidylserine transport from the ER to mitochondrial membranes via ERMES in vitro. Therefore, the Mmm1-Mdm12 complex functions as a minimal unit that mediates lipid transfer between membranes.


Assuntos
Retículo Endoplasmático/metabolismo , Kluyveromyces/metabolismo , Proteínas de Membrana/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Complexos Multiproteicos/metabolismo , Fosfolipídeos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transporte Biológico Ativo/fisiologia , Retículo Endoplasmático/genética , Kluyveromyces/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Complexos Multiproteicos/genética , Fosfolipídeos/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Relação Estrutura-Atividade
8.
Sci Rep ; 7(1): 13780, 2017 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-29062024

RESUMO

Antibody-dependent cellular cytotoxicity (ADCC) is promoted through interaction between the Fc region of immunoglobulin G1 (IgG1) and Fcγ receptor IIIa (FcγRIIIa), depending on N-glycosylation of these glycoproteins. In particular, core fucosylation of IgG1-Fc N-glycans negatively affects this interaction and thereby compromises ADCC activity. To address the mechanisms of this effect, we performed replica-exchange molecular dynamics simulations based on crystallographic analysis of a soluble form of FcγRIIIa (sFcγRIIIa) in complex with IgG1-Fc. Our simulation highlights increased conformational fluctuation of the N-glycan at Asn162 of sFcγRIIIa upon fucosylation of IgG1-Fc, consistent with crystallographic data giving no interpretable electron density for this N-glycan, except for the innermost part. The fucose residue disrupts optimum intermolecular carbohydrate-carbohydrate interactions, rendering this sFcγRIIIa glycan distal from the Fc glycan. Moreover, our simulation demonstrates that core fucosylation of IgG1-Fc affects conformational dynamics and rearrangements of surrounding amino acid residues, typified by Tyr296 of IgG1-Fc, which was more extensively involved in the interaction with sFcγRIIIa without Fc core fucosylation. Our findings offer a structural foundation for designing and developing therapeutic antibodies with improved ADCC activity.


Assuntos
Fucose/química , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulina G/metabolismo , Polissacarídeos/química , Receptores de IgG/química , Receptores de IgG/metabolismo , Cristalografia por Raios X , Glicosilação , Humanos , Imunoglobulina G/química , Simulação de Dinâmica Molecular , Conformação Proteica
9.
Yakugaku Zasshi ; 136(1): 113-20, 2016.
Artigo em Japonês | MEDLINE | ID: mdl-26725678

RESUMO

  Molecular simulations have been widely used in biomolecular systems such as proteins, DNA, etc. The search for stable conformations of proteins by molecular simulations is important to understand the function and stability of proteins. However, finding the stable state by conformational search is difficult, because the energy landscape of the system is characterized by many local minima separated by high energy barriers. In order to overcome this difficulty, various sampling and optimization methods for the conformation of proteins have been proposed. In this study, we propose a new conformational search method for proteins based on a genetic algorithm. We applied this method to an α-helical protein. We found that the conformations obtained from our simulations are in good agreement with the experimental results.


Assuntos
Descoberta de Drogas , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas/química , Algoritmos , Conformação Proteica em alfa-Hélice , Dobramento de Proteína , Estabilidade Proteica , Proteínas/genética
11.
Angew Chem Int Ed Engl ; 53(41): 10941-4, 2014 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-25196214

RESUMO

Exploration of the conformational spaces of flexible biomacromolecules is essential for quantitatively understanding the energetics of their molecular recognition processes. We employed stable isotope- and lanthanide-assisted NMR approaches in conjunction with replica-exchange molecular dynamics (REMD) simulations to obtain atomic descriptions of the conformational dynamics of high-mannose-type oligosaccharides, which harbor intracellular glycoprotein-fate determinants in their triantennary structures. The experimentally validated REMD simulation provided quantitative views of the dynamic conformational ensembles of the complicated, branched oligosaccharides, and indicated significant expansion of the conformational space upon removal of a terminal mannose residue during the functional glycan-processing pathway.


Assuntos
Manose/química , Oligossacarídeos/química , Configuração de Carboidratos , Elementos da Série dos Lantanídeos/química , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular
12.
J Chem Phys ; 138(6): 064103, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23425457

RESUMO

Many commonly used force fields for protein systems such as AMBER, CHARMM, GROMACS, OPLS, and ECEPP have amino-acid-independent force-field parameters for main-chain torsion-energy terms. Here, we propose a new type of amino-acid-dependent torsion-energy terms in the force fields. As an example, we applied this approach to AMBER ff03 force field and determined new amino-acid-dependent parameters for ψ (N-C(α)-C-N) and ζ (C(ß)-C(α)-C-N) angles for each amino acid by using our optimization method, which is one of the knowledge-based approach. In order to test the validity of the new force-field parameters, we then performed folding simulations of α-helical and ß-hairpin peptides, using the optimized force field. The results showed that the new force-field parameters gave structures more consistent with the experimental implications than the original AMBER ff03 force field.


Assuntos
Modelos Moleculares , Proteínas/química , Alanina/química , Aminoácidos/química , Biopolímeros/química , Dobramento de Proteína
13.
J Comput Chem ; 32(7): 1353-60, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21246572

RESUMO

We propose a conformational search method to find a global minimum energy structure for protein systems. The simulated annealing is a powerful method for local conformational search. On the other hand, the genetic crossover can search the global conformational space. Our method incorporates these attractive features of the simulated annealing and genetic crossover. In the previous works, we have been using the Monte Carlo algorithm for simulated annealing. In the present work, we use the molecular dynamics algorithm instead. To examine the effectiveness of our method, we compared our results with those of the normal simulated annealing molecular dynamics simulations by using an α-helical miniprotein. We used genetic two-point crossover here. The conformations, which have lower energy than those obtained from the conventional simulated annealing, were obtained.


Assuntos
Troca Genética , Simulação de Dinâmica Molecular , Proteínas/química , Conformação Proteica , Proteínas/genética
14.
J Org Chem ; 72(25): 9448-55, 2007 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-17979283

RESUMO

Exchange of guest molecules into capsule shaped host molecules is the most fundamental process in host-guest chemistry. Several examples of quantitative measurements of guest exchange rates have been reported. However, there have been no reports on the activation energies of these processes. A molecule known as cavitand-porphyrin (H2CP) has been reported to have a flexible host structure capable of facilitating moderate guest exchange rates suitable for kinetic measurements of the guest exchange process with 1H NMR. In this article, various kinetic and thermodynamic parameters related to the process of encapsulation of small hydrocarbons into H2CP in CDCl3 solution were determined by 2D exchange spectroscopy (EXSY): association and dissociation rate constants (k(ass) = 320 M-1 s-1, k(diss) = 1.4 s-1 for methane at 25 degrees C), the corresponding activation energies (E(a,ass) = 27 kJ.mol-1, E(a,diss) = 58 kJ.mol-1), and thermodynamic parameters for each process (DeltaG++(ass) = 59 kJ.mol-1, DeltaG++(diss) = 72 kJ.mol-1, DeltaH++(ass) = 25 kJ.mol-1, DeltaH++(diss) = 55 kJ.mol-1, DeltaS++(ass) = -113 J.K-1.mol-1, and DeltaH++(diss) = 58 J.K-1.mol-1 for methane). The thermodynamic parameters (DeltaG degrees = -13 kJ.mol-1, DeltaH degrees = -31 kJ.mol-1, DeltaS degrees = -60 J.K-1.mol-1 for methane) for this encapsulation equilibrium determined by EXSY were comparable to those for methane determined by 1D 1H NMR titration (DeltaG degrees = -11 kJ.mol-1, DeltaH degrees = -33 kJ.mol-1, DeltaS degrees = -75 J.K-1.mol-1 for methane). In addition, the structure of the methane encapsulation process was revealed by ab initio MO calculations. The activation energies for methane association/dissociation were estimated from MP2 calculations (E(a,ass) = 58.3 kJ.mol-1, E(a,diss) = 89.1 kJ.mol-1, and DeltaH degrees = -30.8 kJ.mol-1). These values are in accord with the experimentally determined values. The observed guest exchange rates and energies are compared with the corresponding values of various reported capsule-shaped hosts.


Assuntos
Éteres Cíclicos/química , Hidrocarbonetos/química , Porfirinas/química , Resorcinóis/química , Cinética , Espectroscopia de Ressonância Magnética/métodos , Modelos Químicos , Conformação Molecular , Estereoisomerismo , Termodinâmica
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